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On Location
DVT Increases Health-Care Burden and Mortality in Patients With Cancer
Patients with cancer and deep vein thrombosis
(DVT) experience higher rates of hospitalization
and mortality, are less frequently treated with
thrombolysis, and experience gastrointestinal (GI)
bleeds more frequently compared with patients
with DVT in the absence of underlying malignancy,
according to a study presented by lead
Table 6. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Follicular
Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101
(continued)
a
Includes fatigue and asthenia
b
Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper repiratory tract
infection, viral upper respiratory tract infection
c
Includes bronchitis, lower respiratory tract infection, tracheobronchitis
d
Includes cystitis, urinary tract infection, urinary tract infection staphylococcal
e
Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper
f
Includes back pain, limb discomfort, musculoskeletal chest pain, musculoskeletal
discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain,
pain in extremity, pain in jaw, spinal pain
g
Includes erythema, rash, rash erythematous, rash generalized, rash maculo-papular,
rash pruritic, rash pustular, skin exfoliation
h
Includes cough and productive cough
i
Includes headache, migraine, sinus headache
Clinically relevant adverse reactions occurring in <10% of patients who received
TAZVERIK included:
• Infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%)
Table 7 summarizes select laboratory abnormalities in patients with follicular lymphoma
in Cohorts 4 and 5 of Study E7438-G000-101.
Table 7. Select Laboratory Abnormalities (≥10%) Worsening from Baseline
in Patients with Relapsed or Refractory Follicular Lymphoma Who Received
TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101
Laboratory Abnormality
Hematology
TAZVERIK*
All Grades (%) Grade 3 or 4 (%)
Decreased lymphocytes 57 18
Decreased hemoglobin 50 8
Decreased platelets 50 7
Decreased white blood cells 41 9
Decreased neutrophils 20 7
Chemistry
Increased glucose 53 10
Increased aspartate aminotransferase 24 0
Increased alanine aminotransferase 21 2.3
Increased alkaline phosphatase 18 1.0
Increased creatinine 17 0
* The denominator used to calculate the rate varied from 88 to 96 based on the number
of patients with a baseline value and at least one post-treatment value.
DRUG INTERACTIONS
Effect of Other Drugs on TAZVERIK - Strong and Moderate CYP3A Inhibitors:
Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases
tazemetostat plasma concentrations [see Clinical Pharmacology], which may increase the
frequency or severity of adverse reactions. Avoid coadministration of strong or moderate
CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot
be avoided, reduce TAZVERIK dose [see Dosage and Administration]. Strong and Moderate
CYP3A Inducers: Coadministration of TAZVERIK with a strong or moderate CYP3A inducer
may decrease tazemetostat plasma concentrations [see Clinical Pharmacology], which
may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate and strong
CYP3A inducers with TAZVERIK.
Effect of TAZVERIK on Other Drugs - CYP3A Substrates: Coadministration of TAZVERIK
with CYP3A substrates, including hormonal contraceptives, can result in decreased
concentrations and reduced efficacy of CYP3A substrates [see Use in Specific Populations,
Clinical Pharmacology].
USE IN SPECIFIC POPULATIONS
Pregnancy - Risk Summary: Based on findings from animal studies and its mechanism
of action [see Clinical Pharmacology], TAZVERIK can cause fetal harm when administered
to pregnant women. There are no available data on TAZVERIK use in pregnant women to
inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits
during organogenesis resulted in dose-dependent increases in skeletal developmental
abnormalities in both species beginning at maternal exposures approximately 1.5 times
the adult human exposure [AUC 0-45h] at the 800 mg twice daily dose (see Data). Advise
pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized pregnancies
is 2% to 4% and 15% to 20%, respectively.
Data - Animal Data: In pregnant rats, once daily oral administration of tazemetostat during
the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal
adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human
exposure at 800 mg twice daily). Skeletal malformations and variations occurred in fetuses
at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg
twice daily dose). At 200 mg/kg (approximately 14 times the adult human exposure at
the 800 mg twice daily dose), major findings included increased post implantation loss,
author Sheeba Habeeb Ba Aqeel, MD, of the John
H. Stroger, Jr. Hospital of Cook County in Chicago
as part of the ASCO20 Virtual Scientific Program.
According to Dr. Ba Aqeel and colleagues,
pulmonary embolism is an important cause of
increased mortality in patients with cancer. Few
large studies have compared the risk of mortality
missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced
fetal body weights. In pregnant rabbits, no adverse maternal effects were observed after
once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the
adult human exposure at the 800 mg twice daily dose) from GD 7 through 19. Skeletal
variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human
exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day
(approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). At 400
mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose),
major findings included increased post implantation loss and cleft palate and snout.
Lactation - Risk Summary: There are no animal or human data on the presence of
tazemetostat in human milk or on its effects on the breastfed child or milk production.
Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed
child, advise women not to breastfeed during treatment with TAZVERIK and for one week
after the final dose.
Females and Males of Reproductive Potential - Pregnancy Testing: Verify the
pregnancy status of females of reproductive potential prior to initiating TAZVERIK [see Use
in Specific Populations]. Risk Summary: TAZVERIK can cause fetal harm when administered
to pregnant women [see Use in Specific Populations]. Contraception: Females - Advise
females of reproductive potential to use effective non-hormonal contraception during
treatment with TAZVERIK and for 6 months after the final dose. TAZVERIK can render some
hormonal contraceptives ineffective [see Drug Interactions]. Males - Advise males with
female partners of reproductive potential to use effective contraception during treatment
with TAZVERIK and for at least 3 months after the final dose.
Pediatric Use - The safety and effectiveness of TAZVERIK in pediatric patients aged less
than 16 years have not been established.
Juvenile Animal Toxicity Data - In a 13-week juvenile rat toxicology study, animals were
dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to
adulthood). Tazemetostat resulted in:
• T-LBL at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the
800 mg twice daily dose)
• Increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult
human exposure at the 800 mg twice daily dose)
• Increased body weight at doses ≥50 mg/kg (approximately equal to the adult human
exposure at the 800 mg twice daily dose)
• Distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult
human exposure at the 800 mg twice daily dose)
Geriatric Use - Clinical studies of TAZVERIK did not include sufficient numbers of patients
with relapsed or refactory follicular lymphoma aged 65 and over to determine whether they
respond differently from younger subjects.
Renal Impairment - No dose adjustment of TAZVERIK is recommended for patients with
mild to severe renal impairment or end stage renal disease [see Clinical Pharmacology].
Hepatic Impairment - No dose adjustment of TAZVERIK is recommended for patients
with mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal [ULN]
or AST > ULN). TAZVERIK has not been studied in patients with moderate (total bilirubin
> 1.5 to 3 times ULN) or severe (total bilirubin > 3 times ULN) hepatic impairment [see
Clinical Pharmacology].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility - Dedicated carcinogenicity
studies were not conducted with tazemetostat, but T-LBL, MDS, and AML have been
reported clinically and T-LBL occurred in juvenile and adult rats after ~9 or more weeks of
tazemetostat administration during 13-week toxicity studies. Based on nonclinical studies
in rats, the risk of T-LBL appears to be greater with longer duration dosing. Tazemetostat did
not cause genetic damage in a standard battery of studies including a screening and pivotal
bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human
peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral
administration. Fertility and early embryonic development studies have not been conducted
with tazemetostat; however, an assessment of male and female reproductive organs were
included in 4- and 13-week repeat-dose toxicity studies in rats and Cynomolgus monkeys.
Oral daily administration of tazemetostat did not result in any notable effects in the adult
male and female reproductive organs [see Use in Specific Populations].
PATIENT COUNSELING INFORMATION - Advise the patient to read the FDA-approved
patient labeling (Medication Guide).
Secondary Malignancies - Advise patients of the increased risk of secondary malignancies,
including AML, MDS, and T-LBL. Advise patients to inform their healthcare provider if they
experience fatigue, easy bruising, fever, bone pain, or paleness [see Warnings and Precautions].
Embryo-Fetal Toxicity - Advise pregnant women and females of reproductive potential of
the potential risk to a fetus. Advise females to inform their healthcare provider of a known
or suspected pregnancy [see Use in Specific Populations]. Advise females of reproductive
potential to use effective non-hormonal contraception during treatment with TAZVERIK
and for 6 months after the final dose [see Use in Specific Populations]. Advise males with
female partners of reproductive potential to use effective contraception during treatment
with TAZVERIK and for 3 months after the final dose [see Use in Specific Populations,
Nonclinical Toxicology].
Lactation - Advise women not to breastfeed during treatment with TAZVERIK and for
1 week after the final dose [see Use in Special Populations].
Drug Interactions - Advise patients and caregivers to inform their healthcare provider of
all concomitant medications, including prescription medicines, over-the-counter drugs,
vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit, and
grapefruit juice while taking TAZVERIK [see Drug Interactions].
Brief Summary [06/2020]
TZ-FL-BR-20-0109
Rx Only
© 2020 Epizyme ® , Inc. All Rights Reserved.
and health-care burden from DVT and pulmonary
embolism in patients with cancer compared with
patients without cancer.
The study included 404,121 adults from the
Nationwide Emergency Department Sample
(NEDS) database who received a diagnosis of
acute DVT between January 2016 and December
2017. The risk of admission from
the emergency department (ED) as
well as the risk of inpatient mortality
was compared between patients
with cancer and DVT versus patients
with DVT but without cancer in
univariate and multivariate logistic
regression analyses. Secondary outcomes
in this study included hospital
length of stay (LOS), inpatient hospital
charges, GI bleed risk, and rates of
inferior vena cava (IVC) filter placement
and thrombolysis.
Approximately 8% (n=32,330) of
patients in the overall cohort had an
underlying malignancy, most commonly
cancers of the GI tract (20.1%),
hematologic malignancies (16.5%),
and lung cancers (13.5%). Patients
with any form of cancer were older on
average (66.4 vs. 59.8 years) and more
likely to be men (51.8% vs. 47.5%)
than patients with DVT but no cancer.
Patients with cancer and DVT
were more likely to be admitted from
the ED compared with those without
cancer (70.5% vs. 39.1%; odds
ratio [OR] = 3.71; 95% CI 3.41-4.04;
p<0.0001), and had to haved a higher
mortality risk, even after adjustment
for age and comorbidities (OR=3.09;
95% CI 2.42-3.94; p<0.001) as well as
higher GI bleed rates (OR=1.75; 95%
CI 1.45-2.12; p<0.001).
In addition, patients with cancer
and DVT had higher rates of IVC
filter placement (15.2% vs. 9.4%) and
lower rates of treatment with thrombolysis
(4.5% vs. 7.4%), which the
investigators explained might have
been attributable to the higher rates
of concomitant GI bleeding.
The investigators noted that while
primary prophylaxis for venous thromboembolism
in patients with cancer
remains controversial, the high morbidity,
mortality, and health-care burden
from thrombosis in this population
indicates a need for additional research.
The authors report no relevant conflicts
of interest.
Reference
Aqeel SHB, Lingamaneni P, Farooq MZ, et al. Nationwide
analysis of healthcare burden and risk of mortality in cancer
patients with deep venous thrombosis. Abstract e19093.
Presented as part of the 2020 ASCO Virtual Scientific
Program, May 29-31, 2020.
July 2020 Bonus Mid-Year Edition